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Regulator of G protein Signaling 6 (RGS6) Modulates Doxorubicin‐induced DNA Damage Signaling by Regulating ATM Activity
Author(s) -
Huang Jie,
Chatterjee Tapan K,
Mayuzumi Daisuke,
Fisher Rory A
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.706.1
Subject(s) - gene knockdown , dna damage , microbiology and biotechnology , biology , phosphorylation , cancer research , chemistry , genetics , dna , gene
RGS proteins are well known negative regulators of heterotrimeric G protein signaling. We have shown previously that RGS6 sensitizes breast cancer cells to doxorubicin (Dox)‐induced DNA damage signaling (ATM and p53 phosphorylation), suggesting a possible role of RGS6 in tumor suppression. Unexpectedly, these actions of RGS6 were not dependent on its interaction with G proteins. Here we further reveal the mechanism by which RGS6 modulates DNA damage signaling. Expression of a dominant negative form of ATM completely blocked the ability of RGS6 to promote p53 phosphorylation in response to a submaximal dose of Dox in MCF7 cells. Thus, RGS6‐induced activation of p53 is dependent upon ATM activity. Moreover, ATM co‐immunoprecipitates with RGS6 under basal conditions, demonstrating that these two proteins form a complex without induction of DNA damage. RGS6 does not enhance phosphorylation of CHK2 in response to Dox suggesting that RGS6 interactions with ATM may modulate its activity on specific substrates. RGS6 knockdown in MCF7 cells by RNAi significantly reduces p53 activation in response to Dox, demonstrating that RGS6 is required, at least in part, for Dox‐induced DNA damage signaling. Our data indicate that RGS6 plays an important role in modulating chemosensitivity in cancer cells and identify RGS6 as a novel chemotherapeutic target. (NIH GM075033 )